Cytomegalovirus (CMV) is now the leading infectious cause of congenital malformation in the developed world and is largely unrecognised by parents and clinicians. Primary maternal CMV infection or reactivation/infection with a different viral strain may cause adverse pregnancy outcomes including fetal death in utero, sensorineural hearing loss and mental disability in infants infected in utero. Placental infection may also indirectly cause injury to the fetus, possibly via impairing placental development and function. New approaches are urgently needed, as available antivirals are generally not recommended during pregnancy, due to their toxicity and limited efficacy. A better understanding of the molecular mechanisms of CMV infection of the placenta and fetus is essential for therapeutic innovations to decrease the prevalence and societal impact of congenital CMV.
We investigated the effect of human CMV infection on Wnt signalling, a key cellular pathway critically involved in human placentation. In doing so, we show that CMV infection inhibits Wnt5a-mediated trophoblast migration and alters both mRNA and protein expression of the novel Wnt receptor ROR2. Ectopic expression of ROR2 inhibited Wnt5a-mediated trophoblast migration. Utilising small interfering RNA (siRNA) targeting ROR2, we also show that prevention of ROR2-induction by CMV partially rescues virus-inhibited trophoblast migration. Our novel findings suggest that CMV infection may control the expression of the Wnt receptor ROR2 to regulate trophoblast motility, which could lead to abnormal placental development in congenital CMV disease.